Preparing useful derivatives of paraminophenol



Patented June 10, 1924.

untrue stares tame EUGENE THEIMEE, E NEWARK, NEW .1 M

Jeni"! MIGN'QR, BY MESNE ASSIGNMENTS,

TO ROY F. STEWARD, 0F WASHINGTQH', DISTRICT OF CQLUMEIA.

PREPARING USWUL DERIVATIVES 0? its Ito Drawing. Application filed September 5, 1918, serial Kc. 252,722. Renewed December 27, 1923.

To all whom it may concem:

Be it known that I, EUGENE THEIMER, a citizen of the United States, residin at Newark, in the county of Essex and tate e of New Jersey, have invented certain new and useful Improvements in Preparing Useful Derivatives of Paraminophenol; and I do hereby declare the following to be a full, clear, and exact description of the invention, such as will enable others skilled in the art to which it appertains to make and use the same.

This invention'relates to methods of preparing useful derivatives of paraminophe- 1101; and it has to do more particularly with methods of alkylating compounds such as phenacetin and the like.

A principal object of the invention is to efi'ect alkylation of compounds of the general type referred to in a smoother and more controllable procedure than has been available heretofore; and in doing this, an alkylating agent in gaseous form is most de-' sirably employed. Precautions are also taken to maintain the reaction mass in the form of a homogeneous liquid or solution durin the alkylating treatment as contrasteg with prior methods wherein products formed in a preliminary stage of the alkylating treatment separated out in crystalline or other solid form and were not in solution when treated with the alkylating l W i H where R is an alkyl group and R, is an acidyl group.

Such compounds may be regarded as derivatives of paraminophenol. Typical com-.

pounds of this class, suitable for use in the present process are:

OCH:

CH2 C Ho Acetphenetidin 'Acetylanisidin Formylanisidln (phenaeetin) ciples of. the invention hereinafter, a pro- 3 cedure involving the use of phenacetin will therefore be described iii detail for the sake of a concrete example iliustrating what I now believe to be the best mode of practicing the invention.

For the sake of convenience the proportions of the various materials employed are herein given in terms of mols, it being understood that these simply represent the best reacting proportions now known to me and that sald proportions may be varied within the scope of the invention while still realizing the benefits thereof in some measure.

, In the specific example given for purposes of illustration, one mol of acetphenetidin, or phenacetin, is dissolved in a sufiicient quantity of, hot xylol, the amount of xylol most desirably being from three to four parts by wei it of the phenacetin. To the liquid mass, est contained in a suitable reaction vessel provided with a .refiux con-- denser and a stirrer, is then added about one molof an alkali metal in available form, most desirably in the form of the free alkali metal such as metallic sodium in lumps. The reaction begins promptly, the sodium dissolving rapidly and the heat of the reaction being sufilcient to maintain the reaction active until near the end when mod erate external heating may usually be resorted to with advantage.

Towards the end of the reaction the liquid mixture congeals to a white mass, which does not dissolve even upon addition of more hot xylol and continued heating. This mass, which is more or less crystalline, is principally the intermediate sodium compound of m phenacetin, mixed with xylol, the mass containing small particles of unchanged metallic sodium. In order to complete the reaction and also to place the mass in proper condition for subsequent treatment with a gaseous alkylatin agent, methyl bromid being especially a vantageous to employ, it is very desirable to have the mixture completel in li uid condition. At this stage, I there ore a d to the mass a substance capable of liquefying the same. For this purpose I have found that one of the later reaction products, methyl phenacetin, acts in a peculiarly efiective manner, an addition of from to per cent of methyl phenacetin, based on the weight of the conealed mass, being amply sufiicient to bring t e whole mixture into solution very rapidly, whereupon substantially all the residual metallic sodium enters into combination excepting possibly small traces which are removed by filtration at a later stage of the OOzHs cz o KNW The hot solution is filtered carefully to separate the recipitated sodium bromid and also such 5 ight traces of metallic sodium as may still remain unchanged. Special care should be exercised in this filtration to see that all traces of metallic sodium are actuaccordingly.

ally removed. This is necessary in order to avoid trouble in the subsequent steam distillation of the filtrate. From the filtrate, the solvent xylol is now distilled off with steam and may be recovered in any appropriate or well known manner. The Oil remaining from the steam distillation is meth l phenacetin. It may desirably be puri ed y distillation in vacuo.

The use of meth 1 bromid, in the foregoing procedure 0 ers special advantages because by its use the methylating operation can be conducted much more smoothly and with greater ease of control than would be the case if a liquid methylating agent, such as methyl iodid, were employed. Although the s eed of reaction is greater when methyl iodi is used, great care has to be exercised to add the reagent very gradually drop by drop in order to avoid violent ebull1-- tion of the reaction mixture due to the sudden transformation of liquid methyl iodid into vapor as the liquid is dropped into the hot reaction mass. This trouble is one which it is dificult to avoid under ordinary operating conditions, as a considerable proportion of the methyl iodid is volatilized upon contact with the hot reaction mass and leaves the latter unchanged, but is then caught by the reflux condenser and returned as liquid to the reaction mixture, thus again undergoing sudden and violent transformation into vapor. with a re etition of the same disturbances. These di culties are entirel overcome when methyl bromid is employe Moreover, contrary to what would be expected, the gaseous methyl bromid is quantitatively absorbed as fast as it is introduced into the reaction mixture, notwithstanding that the latter is very hot.

Variations in detail from the specific procedure above described by way of explanatory exam 1e can evidently be practiced within the road scope of the invention, and the appended claims are to be interpreted What claim is:

1. In the preparation of useful derivatives of paraminophenol, the process which comprises converting phenacetin into the sodium compound thereof, and treating said sodium compound with gaseous methyl bromid.

2. In the preparation of useful derivatives of paraminophenol, the process which comprises treating a solution of henacetin in an inert solvent with metall1c sodium, adding methyl phenacetin to the reaction mass, and passing methyl bromid into the mixture.

3. In the preparation of useful derivatives of paraminophenol the process which comprises dissolving phenacetin in a solvent, adding metallic sodium, adding a liquef'ying agent to the reaction mixture, passing methyl bromid into the liquid mass,

and separating resultant methyl henacetm.

4. In the preparation of use 111 derivatives of paraminophenol, the .process which comprises converting phenacetin into an alkali metal compound thereof, and methylating said compound while in liquid condition with a gaseous methylatin agent."

5. In the preparation of useful erivative's of paraminophenol, the process which comprises converting a compound having the type formula sub ecting a liquid mixture of an alkali' metal compound of phenacetin with an inert kali metal bromid from the resultant methyl solvent and an agent preventing solidification of said alkali metal compound, to the action of a gaseous alkylating agent.

7. In the preparation of useful derivatives of paraminophenol the process-which comprises passing a gaseous alkylating agent.

into a homogeneous liquid reaction mass comprising an alkali metal derivative ofa compound having the type'formula n (where R, is an alkyl group and R is an acidyl group). i

8. In the preparation of methyl phenacetin, the process which comprises passing gaseous methyl bromid into a mixturecom-' prising an alkali metal derivative of phenacetin and a liquid diluent, and separating alphenacetin.

9. In the preparation of alkyl derivatives of phenacetm, the process which comprises preparing a liquid mixture comprising an alkali metal derivative of phenacetin and an alkyl derivative of phenacetin, andthen subjecting said mixture to the action of an alkylating agent.

10. In the pre aration of al I derivatives of phenacetin, t 'e process which comprises preparing a liquid mixture comprising an with a free alkali meta free alkali metal being remove action of an alkylatingagent.

- 11. In the preparation of methyl phenacetin, the process which comprises preparing a liquid mixture com rising sodium phenacetin and methyl p enacetin, and then subjecting said mixture to the action of a methyl halid. 12. In the preparation of methyl phenacetin, the process which comprises preparing a liquid mixture comprising sodium phcnacetin, methyl phenacetm, and xylol, and then subjecting said mixture to the action of methylbromid.

13. In the preparation of alkyl derivatives of phenolic compounds the process which comprises preparing a liquid mixture comprising an alkali metal derivative of the 7 organic compound to be .alkylated and an alkyl derivative of said organic com und, and then subjecting said mixture to t e action of an alkylating agent.

14. In the preparation of alkyl derivatives of compounds of the paraminophenol type, the process which comprises preparing a liquid mixture comprising an alkali metal derivative of a compound of the paraminophenol ty and an a l derivative of said compoun and then su jectingthe mixture to the action of an alkylating agent.

15. In the preparation of alkyl derivatives of prganic compounds having the type formu a 7 x where R, is an alkyl group and R is an acidyl group, the process which comprises preparing a liquid mixture comprising an alkali metal derivative of such an organic compound and an alkyl derivative of said organic compound, and then subjecting said mixture to the action of an alkylating agent. '16. In the reparation of alkyl derivatives of compoun s of the paraminophenol type, the process whichcomprises preparing a liquid mixture comprising an alkali metalderivative of a compound of the paraminophenol type, an alk l derivative of said compound, and a liquid diluent, such preparation including the step of reacting upon said compound of the araminophenol type i subjecting said liquid mixture to the action of an alkylating agent, andseparating said liquid diluent from the resultant desired alkyl derivative by steam distillation, residual from the articles of Meagan mixture at a stage prior tosuch distillation. ther characterized by the fact that said liq- 17. The process as defined in claim 7, furuid reaction mass is malntained near its ther characterized by the factthat said liqboiling temperature during passage of the W uid reaction mass is maintained hot during gaseous alkylatin agent thereinto.

a passage of the gaseous alkylating agent In testimony w ereof I hereunto afiix my 'thereinto. signature.

1s. The process as defined in claim 7, fur EUGENE THEIMER. 

